Eivind Hennestad

• Gianatti, Michele; Garvert, Anna Christina; Lenkey, Nora Melinda; Ebbesen, Nora Cecilie; Hennestad, Eivind & Vervaeke, Koen Gerard Alois (2023). Multiple long-range projections convey position information to the agranular retrosplenial cortex. Cell reports. 42(9). doi: 10.1016/j.celrep.2023.113109. Full text in Research Archive Show summary

  Neuronal signals encoding the animal’s position widely modulate neocortical processing. While these signals are assumed to depend on hippocampal output, their origin has not been investigated directly. Here, we asked which brain region sends position information to the retrosplenial cortex (RSC), a key circuit for memory and navigation. We comprehensively characterized the long-range inputs to agranular RSC using two-photon axonal imaging in head-fixed mice performing a spatial task in darkness. Surprisingly, most long-range pathways convey position information, but with notable differences. Axons from the secondary motor and posterior parietal cortex transmit the most position information. By contrast, axons from the anterior cingulate and orbitofrontal cortex and thalamus convey substantially less position information. Axons from the primary and secondary visual cortex contribute negligibly. This demonstrates that the hippocampus is not the only source of position information. Instead, the RSC is a hub in a distributed brain network that shares position information.

• Bjørnstad, Daniel Marelius; Åbjørsbråten, Knut Sindre; Hennestad, Eivind; Cunen, Celine; Hermansen, Gudmund Horn & Bojarskaite, Laura [Show all 9 contributors for this article] (2021). Begonia - a two-photon imaging analysis pipeline for astrocytic Ca2+ signals. Frontiers in Cellular Neuroscience. 15. doi: 10.3389/fncel.2021.681066. Full text in Research Archive Show summary

  Imaging the intact brain of awake behaving mice without the dampening effects of anesthesia, has revealed an exceedingly rich repertoire of astrocytic Ca 2+ signals. Analyzing and interpreting such complex signals pose many challenges. Traditional analyses of fluorescent changes typically rely on manually outlined static region-of-interests, but such analyses fail to capture the intricate spatiotemporal patterns of astrocytic Ca 2+ dynamics. Moreover, all astrocytic Ca 2+ imaging data obtained from awake behaving mice need to be interpreted in light of the complex behavioral patterns of the animal. Hence processing multimodal data, including animal behavior metrics, stimulation timings, and electrophysiological signals is needed to interpret astrocytic Ca 2+ signals. Managing and incorporating these data types into a coherent analysis pipeline is challenging and time-consuming, especially if research protocols change or new data types are added. Here, we introduce Begonia, a MATLAB-based data management and analysis toolbox tailored for the analyses of astrocytic Ca 2+ signals in conjunction with behavioral data. The analysis suite includes an automatic, event-based algorithm with few input parameters that can capture a high level of spatiotemporal complexity of astrocytic Ca 2+ signals. The toolbox enables the experimentalist to quantify astrocytic Ca 2+ signals in a precise and unbiased way and combine them with other types of time series data.

• Hennestad, Eivind; Witoelar, Aree Widya; Chambers, Anna Ruth & Vervaeke, Koen Gerard Alois (2021). Mapping vestibular and visual contributions to angular head velocity tuning in the cortex. Cell reports. 37(12). doi: 10.1016/j.celrep.2021.110134. Full text in Research Archive Show summary

  Neurons that signal the angular velocity of head movements (AHV cells) are important for processing visual and spatial information. However, it has been challenging to isolate the sensory modality that drives them and to map their cortical distribution. To address this, we develop a method that enables rotating awake, head-fixed mice under a two-photon microscope in a visual environment. Starting in layer 2/3 of the retrosplenial cortex, a key area for vision and navigation, we find that 10% of neurons report angular head velocity (AHV). Their tuning properties depend on vestibular input with a smaller contribution of vision at lower speeds. Mapping the spatial extent, we find AHV cells in all cortical areas that we explored, including motor, somatosensory, visual, and posterior parietal cortex. Notably, the vestibular and visual contributions to AHV are area dependent. Thus, many cortical circuits have access to AHV, enabling a diverse integration with sensorimotor and cognitive information.

• Morland, Cecilie; Andersson, Krister; Haugen, Øyvind Pernell; Hadzic, Alena; Kleppa, Liv & Gille, Andreas [Show all 21 contributors for this article] (2017). Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. Nature Communications. 8. doi: 10.1038/ncomms15557. Full text in Research Archive Show summary

  Physical exercise can improve brain function and delay neurodegeneration; however, the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 enhances cerebral vascular endothelial growth factor A (VEGFA) and cerebral angiogenesis. High-intensity interval exercise (5 days weekly for 7 weeks), as well as L-lactate subcutaneous injection that leads to an increase in blood lactate levels similar to exercise, increases brain VEGFA protein and capillary density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle shows no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. Thus, we demonstrate that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor. Editorial summary: Physical exercise promotes brain angiogenesis through an unknown signalling cascade. Morland et al. identify the elusive muscle-brain communication and show that lactate produced by muscle activity binds to its receptor HCAR1 in brain vessel-surrounding cells, stimulating VEGF production and brain angiogenesis.

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• Benediktsdottir, Signy; Golla, Archana; Blixhavn, Camilla Hagen; Hennestad, Eivind; Kleven, Heidi & Najafi, Peyman [Show all 16 contributors for this article] (2024). Towards FAIR neuroscience: an efficient workflow for sharing and integrating data. Full text in Research Archive
• Pieschnik, Sophia; Golla, Archana; Reiten, Ingrid; Schlegel, Ulrike; Hennestad, Eivind & Hübenette, Saira Jameela [Show all 20 contributors for this article] (2023). Pioneering open neuroscience - the role of the curation services. Full text in Research Archive
• Andersson, Krister; Morland, Cecilie; Haugen, Øyvind Pernell; Hadzic, Alena; Kleppa, Liv & Gille, Andreas [Show all 21 contributors for this article] (2017). Exercise benefits brain through the lactate receptor HCAR1, increasing VEGF and capillary density in hippocampus and cortex. Full text in Research Archive Show summary

  While physical exercise is known to improve brain function and delay neurodegeneration, the signal from muscle to brain has not been identified. We show here that the lactate receptor, hydroxycarboxylic acid receptor 1 (HCAR1 also known as GPR81), mediates exercise induced increase in the content of vascular endothelial growth factor A (VEGFA) and in capillary density in the hippocampus and cerebral cortex. Mice were subjected to high intensity interval exercise 5 days per week for 7 weeks. Increases in VEGFA and capillary density were observed in wild-type (wt) mice, but not in knockout (ko) mice lacking HCAR1. Subcutaneous injections of L-lactate 5 days per week for 7 weeks, to achieve intermittently high blood lactate levels comparable to those after exercise, reproduced the findings in wt mice. No changes were observed in ko mice. The intermittent nature of the stimulation may be important since continuously high extracellular lactate has previously been observed to down-regulate HCAR1. To our knowledge, the present finding is the first demonstration that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor. No changes in VEGFA or capillary density were observed in the cerebellar cortex. HCAR1 was highly expressed in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in fibroblast-/pericyte-like cells along intracerebral microvessels. These cells are strategically placed to monitor changes in blood-born lactate as well as in brain extracellular lactate (which equilibrate across the vascular endothelium via monocarboxylate transporter 1). Skeletal muscle showed no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. As VEGFA governs neuronal functions such as LTP as well as vascular growth, the increases may have direct effects on neurons as well as indirect effects through enhancement of vascularization. Both disturbed vascularization and impaired synaptic function are components of the pathogenesis in neurodegenerative dementias such as Alzheimer’s disease. The lactate receptor HCAR1 may prove a useful nutraceutical target for intervention in persons at risk for dementia who are unable to exercise sufficiently to achieve optimal HCAR1 stimulation through rises in blood lactate.

• Morland, Cecilie; Andersson, Krister; Haugen, Øyvind Pernell; Hadzic, Alena; Kleppa, Liv & Gille, Andreas [Show all 18 contributors for this article] (2016). A novel mechanism for cerebral angiogenesis via lactate receptor HCAR1 at pial vessels. Full text in Research Archive
• Morland, Cecilie; Andersson, Krister; Haugen, Øyvind Pernell; Hadzic, Alena; Kleppa, Liv & Gille, Andreas [Show all 18 contributors for this article] (2016). Exercise induces cerebral angiogenesis via lactate receptor HCAR1 at pial vessels. Full text in Research Archive

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